OP0106 SYNOVIAL IMPRINTING OF SKIN-DERIVED IMMUNE CELLS INITIATES SPREADING OF INFLAMMATION FROM SKIN TO JOINT IN PSORIATIC ARTHRITIS
Authors: M. G. Raimondo, S. Rauber, H. Mohammadian, M. Vogg, C. Xu, A. Rius Rigau, M. Luber, H. Labinsky, A. Soare, J. Distler, U. Fearon, D. Veale, M. Sticherling, J. D. D. Cañete, G. Schett, A. Ramming
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Spreading of inflammation from skin to joint is still an unsolved key aspect of psoriatic arthritis (PsA) pathogenesis. Psoriasis (PsO) usually anticipates the joint manifestations, suggesting the existence of a disease mediated skin-joint crosstalk. However, only 30% of the patients with psoriasis develop PsA overtime.<sup>[1]</sup> To date, it is still obscure why the inflammatory process in some patients with PsO is restrained to the skin, whereas in other patients it spreads to the joints. <h3>Objectives</h3> Using a pre-clinical model of PsA and PsO, we aimed to investigate the skin-joint axis, i.e. the spreading of psoriatic inflammation from the skin to the joints, and to address its role in PsA pathogenesis. <h3>Methods</h3> The IL-23 overexpression (IL-23OE) mouse model of psoriasis was performed in different genetic backgrounds of KAEDE-transgenic mice expressing a photo-convertible fluorescent reporter to assess cell trafficking from inflamed skin to other organs. Psoriatic skin lesions were irradiated with UV light to trigger the photoswitch from KAEDE<sup>GREEN</sup> to KAEDE<sup>RED</sup>. Migration of immune cells to joints was determined by light sheet fluorescence microscopy (LSFM) and flow cytometry. Imaging flow cytometry was used to determine the phenotype of cells migrating from the skin to other organs. The interactome of skin-derived migrating cells in joints was characterized by single-cell RNA-sequencing (scRNAseq) and functional analyses. Data were validated in synovial biopsies from PsO and PsA patients by imaging mass cytometry. <h3>Results</h3> IL-23 induced initiation of inflammation at the joints was dependent on the genetic background of the mice as assessed by MRI scan and histological analysis. However, migration of immune cells from psoriatic skin to the joints was observed in both strains, protected and non-protected mice from arthritis, although other organs such as spleen and lymph nodes showed no model dependent skin-derived migration. ScRNAseq and computational fate mapping with RNA velocity analysis revealed CD2+ MCHII+ monocytes as predominant cell type escaping the inflamed skin and entering the synovial tissue. In the pre-differentiated stage, those monocytes showed similar phenotypes in both, arthritis protected and non-protected animals. However, after entering the synovial tissue further differentiation into macrophages resulted into two different phenotypes, with pro-inflammatory characteristics in mice developing arthritis. Interactome analyses between local differentiated skin-derived macrophages and tissue resident synovial cells revealed major implication of synovial fibroblasts shaping the fate of skin-derived monocytes into a protective or pro-inflammatory phenotype with capacity to initiate the cascade of inflammation. Imaging mass cytometry of synovial biopsies from patients with PsO and PsA identified niches of the synovial membrane that were protected from inflammation by a similar fibroblastic fate as observed in the murine setting. Protection from arthritis was associated with significantly increased interactions of those protective fibroblasts with innate lymphoid cells (ILC) type 2, inducing pro-survival signals and resulting into activation of pro-resolving ILC2s.<sup>[2]</sup> <h3>Conclusion</h3> Spreading of inflammation from the skin to the joint can be initiated by skin-derived monocytes. However, the interaction between migrating monocytes and stromal-resident cells is essential to define the fate towards joint inflammation or joint protection in PsA. The data might provide completely new diagnostic opportunities to estimate the risk of PsO patients to develop PsA in the future. <h3>References</h3> [1]Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet. 2018 Jun 2;391(10136):2273-2284. [2]Rauber S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat Med. 2017 Aug;23(8):938-944. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.